Autosomal recessive osteopetrosis: mechanisms and treatments

Abstract

Autosomal recessive osteopetrosis (ARO) is a severe inherited bone disease characterized by defective osteoclast resorption or differentiation. Clinical manifestations include dense and brittle bones, anemia and progressive nerve compression, which hamper the quality of patients' lives and cause death in the first 10 years of age. This Review describes the pathogenesis of ARO and highlights the strengths and weaknesses of the current standard of care, namely hematopoietic stem cell transplantation (HSCT). Despite an improvement in the overall survival and outcomes of HSCT, transplant-related morbidity and the pre-existence of neurological symptoms significantly limit the success of HSCT, while the availability of human leukocyte antigen (HLA)-matched donors still remains an open issue. Novel therapeutic approaches are needed for ARO patients, especially for those that cannot benefit from HSCT. Here, we review preclinical and proof-of-concept studies, such as gene therapy, systematic administration of deficient protein, in utero HSCT and gene editing.

Keywords: Bone disease; Gene therapy; Hematopoietic stem cell transplantation; Osteoclast; Osteopetrosis.

Fig. 1.

Schematic representation of genes involved in osteoclast-rich osteopetrosis. The figure shows genes involved in the bone resorptive activity of osteoclasts with different functions, including acidification of resorption lacunae and pH regulation (TCIRG1, CLCN7, OSTM1 and CA2), vesicular trafficking and sorting of protein complexes to the membrane (SNX10 and PLEKHM1), lysosomal nucleoside trafficking (SLC29A3), cytoskeletal rearrangement for ruffled border formation (KINDLIN3, integrin-β and LRRK1) and lysosomal proteolytic cleavage for bone remodeling and resorption (CTSK). Moreover, genes that are involved in different signal transduction pathways and essential for osteoclast function (MITF, TRAF6, RELA and NEMO) have been reported. Figure originally created using Servier Medical Art (http://smart.servier.com/), licensed under a CC-BY 3.0 license, and re-drawn according to journal style.

Fig. 2.

Representation of proteins involved in osteoclast-poor osteopetrosis. Impaired crosstalk between osteoclasts and osteoblasts gives rise to deficient bone remodeling. In osteoclast-poor osteopetrosis, the osteoclast differentiation pathway is impaired due to mutations in the TNFSF11 and TNFRSF11A genes, encoding RANKL and its receptor RANK, respectively, or in the CSF1R gene, encoding M-CSF. As a consequence, osteoclast precursors are not able to fuse and to differentiate into multinucleated resorbing osteoclasts. Mutated genes are indicated by a red cross. Figure originally created using Servier Medical Art (http://smart.servier.com/), licensed under a CC-BY 3.0 license, and re-drawn according to journal style.

Fig. 3.

Current therapeutic approaches for ARO and novel gene therapy strategies for TCIRG1-dependent osteopetrosis. Hematopoietic stem cell (HSC) transplantation (beige box) is the current standard of care: CD34⁺ cells are collected from a compatible healthy donor and infused into the patient, who has previously received myeloablative conditioning. Alternatively, gene therapy represents an innovative approach, allowing autologous HSC transplantation without the risk of graft rejection. Currently, a Phase I clinical trial for TCIRG1-dependent ARO is ongoing (green box): the autosomal recessive osteopetrosis (ARO) patient's CD34⁺ cells are collected and transduced with a lentiviral vector (LV) carrying the curative gene under the control of the elongation factor 1α short (EFS) promoter. The transduced stem cells are later re-infused into the patient after administration of a conditioning regimen. A different approach coupling circulating ARO CD34⁺ cell expansion with LV gene correction has recently been proposed at a preclinical level by our group (blue box). In particular, circulating CD34⁺ cells are collected from the peripheral blood of ARO patients and transduced with an LV carrying the TCIRG1 gene under the control of the phosphoglycerate kinase (PGK) promoter. After transduction, CD34⁺ cells are expanded ex vivo, exploiting the UM171-based HSC expansion protocol, which is able to increase HSC number while maintaining the cells’ stemness and engraftment capacity. The cell product is suitable for cryopreservation, thus providing the possibility to perform multiple cycles of cell infusions. Finally, the transduced and expanded HSCs are re-infused into the patient after administration of a conditioning regimen. Figure originally created using Servier Medical Art (http://smart.servier.com/), licensed under a CC-BY 3.0 license, and re-drawn according to journal style.